In the field of diagnostic medical imaging, complexes of paramagnetic metal ions are widely used as contrast agents. The lanthanide metal ions, especially Gd(III) and Dy(III) are among the most effective MR contrast enhancers and to ensure appropriate biodistribution and post-contrast bioelimination, they are administered in chelate complexes which have very high stability constants. While some of the chelating agents used have a linear polyamine structure (eg. DTPA as in Schering's GdDTPA product Magnevist and DTPA-BMA as in Nycomed Imaging's GdDTPA-BMA product Omniscan), others have a macrocyclic polyamine structure, eg. DOTA as in Guerbet's GdDOTA product Dotarem and HP-D03A as in Squibb's GdHP-D03A product ProHance.
The 1,4,7,10-tetraazacyclododecane (cyclen) polyamine skeleton of DOTA and HP-D03A forms the basis for a range of particularly stable lanthanide-chelating macrocyclic chelants in which three or four of the ring nitrogens carry a pendant, ionizable metal coordinating group, eg. a carboxylic or phosphonic acid group. Since the lanthanide ions of interest are generally in the III state, cyclen-based chelants carrying three such acid groups offer the opportunity to produce charge-neutral or non-ionic chelate complexes. This is of importance since various side effects of contrast agent compositions are associated with hypertonicity and non-ionic contrast agents have a lower contribution to the overall osmolality of the composition.
Recently, Schering and Nycomed Salutar have proposed various "dimeric" macrocyclic chelates in the chelant for which two cyclen rings are linked by a bridge between ring nitrogens. The remaining ring nitrogens in these chelants will generally carry metal coordinating acid groups so that the resultant complex carries two metal ions but again is charge-neutral overall.
Cyclen is a key intermediate in the preparation of such macrocyclic chelating agents, with the ring nitrogens being appropriately substituted after macrocyclic ring formation has occurred.
Thus for example one may produce DOTA (1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid) by reacting cyclen with bromo-acetic acid or its t-butyl ester, in the later case followed by ester cleavage.
Where however one of the ring nitrogens is to carry a different substituent from the other three, use of cyclen leads to yield loss due to the formation of undesired N-substitution products. One approach to this is to mono-substitute cyclen before substituting the three remaining nitrogens; another is to start from a mono-substituted cyclen produced for example by condensing a triamine with a monoamine, with one of the two amine reagents carrying the substituent group (eg. as in the N-monosubstituted cyclen syntheses of Dischino et al., Inorg Chem. 30:1265 (1991), Pilchowski et al Tetrahedron 41: 1956 (1981), and Tweedle et al. (EP-A-232 751 and EP-A-292689)).
The present invention is based on the finding that, for the production of chelating agents comprising triacid substituted cyclen, a particularly straightforward and flexible route is offered via the N,N',N"-tribenzylcyclens, compounds which are themselves novel.